Antigenic changes in cancer cells can be recognized by the immune system of patients themselves and presented as immune responses to factors involved in malignant transformation. This is manifested in several ways, one of which is the appearance of circulating autoantibodies. These autoantibodies, which have been called reporters from the immune system, identify the antigenic changes in cellular factors involved in the transformation process. Circulating autoantibodies from cancer patients have been used to isolate the cognate tissue antigens, many of which have been shown to be cellular factors participating in known tumorigenesis pathways. These cancer-related tissue antigens have been generally called tumor-associated antigens (TAAs). In the case of liver cancer, especially hepatocellular carcinoma (HCC), antecedent liver cirrhosis and chronic hepatitis are common precursor conditions and during transition to malignancy some patients develop novel autoantibodies that were not present during the preceding chronic liver disease phase. The hypothesis is that transition to malignancy can be associated with autoantibody responses to certain cellular proteins that might have some role in tumorigenesis. It is proposed that the information that the cancer patient's immune system is conveying in the form of autoantibodies to TAAs should be utilized to a greater extent in identifying early signs of tumorigenesis. There are three specific aims in this grant application: (1) Establish more precise time lines to determine when autoantibodies to TAAs appear as early predictors of HCC in patients with antecedent chronic viral hepatitis and liver cirrhosis; (2) Identify and characterize novel TAAs in HCC using a proteome-based technology, and further validate the potential value of the identified TAAs as cancer biomarkers; (3) Establish rigorous criteria for designation of an autoantibody to a TAA as a cancer biomarker, examine candidate TAAs for sensitivity and specificity of anti-TAA antibody response, and further develop customized TAA arrays that can be used to enhance anti-TAA antibody detection in HCC.